Glucocorticoids (GCs) are hormones released from the adrenal glands during stress and are well known for their potent and pleiotropic anti-inflammatory effects. In the injured CNS, their anti-inflammatory properties could be beneficial in cases where excessive inflammation imperils neuron survival. It is therefore important to understand specifically how GCs affect the immune response in the brain, especially given emerging evidence that under some circumstances GCs do not decrease inflammation and can even augment aspects of the immune response during CMS injury. It is well established that acute GC exposure can augment localized inflammatory responses while longer-term GC exposure is immunosuppressive. However, chronic GC exposure was recently found to increase CMS infiltration of macrophages, granulocytes, and microglia to excitotoxic injury accompanied by elevated levels of the pro-inflammatory cytokines IL-1(i, TNF-a, and IL-6. Chronic GC exposure was also found to augment CMS signaling of these cytokines and the pro-inflammatory transcription factor NFicB from peripheral exposure to endotoxin. Given their well-known anti-inflammatory properties, it is surprising that GCs do not blunt, but instead increase these inflammatory responses. Based on these findings, it is possible that chronic exposure to GCs augments the inflammatory response in the injured CMS. Chronic GC exposure could elevate CNS inflammation by stimulating any of the GC receptor subtypes in any of the cells present in the CNS. Two different nuclear hormone receptors for GCs exist, namely the GC receptor (GR) and the mineralocorticoid receptor (MR). A GR antagonist blocks the GC-augmented CNS inflammation, implicating the GR in this phenomenon;however it is unclear which cell type(s) are acted on by GCs to cause these pro-inflammatory effects. The most likely neuro-immune targets of GCs are the resident microglia and the peripheral leukocytes that extravasate to the site of injury. Both of these cell types express GR and are instrumental in orchestrating immune responses to acute injury. This proposal is designed to measure immune cell-specific effects of GCs during kainic acid-induced excitotoxicity by using previously characterized leukocyte-specific, GR-knockout mice. We will test the hypothesis that GR signaling in leukocytes is necessary for their increased recruitment and activation. We will also determine whether GR signaling in these cells affects the likelihood of neuron survival. The following aims are proposed to determine which of the observed effects of chronic GCs on inflammation and neuron death can be explained by leukocyte cell-autonomous GR signaling: